The purpose of this project is to investigate the pathogenesis of biochemical and morphologic hepatocellular lesions in experimentally induced porphyria. Experimental porphyria bears many similarities to the human disease, acute intermittent porphyria, including a marked increase in liver alpha-aminolevulinic acid synthetase activity with resultant overproduction of porphobilinogen and alpha-aminolevulinic acid. Of particular interest in this study will be the relationship of nuclear and smooth endoplasmic reticulum changes to specific enzyme induction and to porphyrin precursor overproduction. Experimental models which will be used in the project include rats, chick embryos and primary cultures of chick embryo liver cells. Attempts will be made to establish a mammalian liver cell culture which will respond to specific chemical inducers by increased synthesis of alpha-aminolevulinic acid synthetase. Multiple approaches will be used in the study of these experimental models including electron microscopy, electron microscope autoradiography, and cytochemistry in conjunction with selected biochemical procedures. The latter include assays of alpha- aminolevulinic acid synthetase and endogenous nuclear RNA polymerase activities, determination of chromatin template capacity for DNA- dependent RNA synthesis, examination of chromatin structure by chemical and immunochemical means, and purification of alpha-aminolevulinic acid synthetase, the first and rate-limiting enzyme in porphyrin and heme biosynthesis. Data obtained in this project should also have implications concerning normal liver function and pathologic alterations in other disease states.